Cross‐immunity and trained immunity in explaining variable COVID‐19 mortality—Guidance for future pandemics

COVID-19 mortality and spread have varied widely across countries. It has been quite difficult to explain this variability by restrictive strategies adopted in the different nations. A significant part of this variation may be dependent on biological and environmental factors. In early April we had predicted a low mortality due to COVID-19 in India based on several factors, cross-immunity to endemic coronaviruses being prominent among them. Cross-reactive antibodies as well as T-cells have been later demonstrated by several groups. The importance of this cross-immunity in modifying the spread of COVID-19 in a population and the development of herd immunity has been discussed by us, as well as other authors who in a recent review have elaborated several theoretical models. Other driving factors of this natural variation of COVID severity may be trained immunity and immune tolerance acquired by the innate immune system, both a result of recurrent infections by diverse pathogens. We hypothesize, that in countries like India, huge sections of population, living in crowded and unsatisfactory hygienic conditions, are subjected to repeated infections by viruses, bacteria, and eukaryotic parasites, and this probably leads to a state of 'immune tolerance' in them against a novel organism like SARS-CoV-2. Although at present the major focus is on the detection and containment of COVID-19, including the development of vaccines, it appears that a better understanding of the host's response to SARS-CoV-2 invasion may provide us clues to explain the epidemiology of this pandemic in different countries and formulate nation-specific management plans. This article is protected by copyright. All rights reserved.